Public Funding for Exactmer Limited

Oligonucleotides (oligos) are sequences of nucleotides monomers which usually contain between 15-25 nucleotides/ nucleotide-analogues, they offer promising treatment for a wide range of medical conditions. There are now 15 oligo drugs which have been approved between the EMA and FDA. In recent years, an **increasing number of oligos in clinical trials** have shown excellent results for diseases with large patient populations. For example, Inclisiran, an oligo developed for the treatment of cardiovascular disease (thousands of patients), was approved in Europe in 2020 and is available on the NHS since 2021\. It is estimated Inclisiran will treat 300,000 patients in the UK in the next three years. While Solid Phase Synthesis (SPS) is the dominant manufacturing process to produce oligos it presents several limitations. The main challenges comprise: **the lack of scalability** (~10-20kg batch sizes maximum), the **high costs** (£800-£1000/g of oligos) and the **heavy environmental burden** associated with the process (~4300kg/kg PMI). This creates a critical need for sustainable, ton-per-annum-scale oligo production routes to enable oligos to deliver patient benefits in large populations. The Grand Challenge 'GC3' consortium (comprising Novartis, AstraZeneca, Alnylam, Exactmer, CPI) is developing Nanostar Sieving, a **breakthrough new technology based on Liquid Phase Synthesis** (LPS) to manufacture oligos. For oligo manufacture, this platform is positioned to provide ease of scaling under GMP conditions (100kg/batch), with high crude purity oligos (70-90%) and use of similar phosphoramidite monomer equivalents (1.5 equivalents/cycle). Maximising Efficiency of Liquid-phase Oligo Synthesis (MELOS) is a UK based collaboration between Exactmer, Queen Mary University of London (QMUL), CPI and AstraZeneca, seeking to build on the success of GC3\. This 24-month project will focus on **a step change in the process efficiency and sustainability of the Nanostar Sieving platform** for the synthesis of oligos on large scale. The current chemistry will be further developed by using Nanostar hubs and monomers with better membrane selectivities and higher solubilities. Further step changes include integration of a solvent recycling loop within the Nanostar Sieving process, seeking a **reduction of 40% in the total Process Mass Intensity** (PMI) compared to SPS technology. A solvent drying device will allow in-process water removal that will reduce required phosphoramidites equivalents to close to stoichiometric (i.e., <1.1 equivalents). In-line, real-time analysis will be implemented to monitor the quality of the recycled solvent. Furthermore, this work is required to ensure the **highest quality of product is obtained with minimal environmental impact, and at reduced costs**.

no public description

Polymers are long molecules, comprising repeated chemical units known as monomers. Polyethylene glycol (PEG), comprising ethylene glycol (EG) monomers, is a polymer widely used in biomedicine. PEG is used to improve the water-solubility of drugs and proteins, and to regulate their transport and retention in the body. However, the current EG monomers that make up PEGs are unadaptable; they cannot attach any 'cargo', such as drugs, dyes, or cell-penetrating agents. Consequently, PEGs can only be adapted at the beginning and end of the polymer chains, and not along the polymer backbone, limiting what they can achieve in biomedical applications. Furthermore, current techniques that make polymers on industrial scales do not allow easy control over the monomer sequences, and so even if different, specialised-EG monomers were used, arranging them in a specific order to make bespoke polymers would be challenging, time-consuming and expensive. Exactmer is a fast-growing SME, developing a breakthrough new technology for the fabrication of polymers with exact lengths and monomer sequences: Nanostar Sieving. Hub molecules with multiple arms forms large 'nanostars'. Monomers are added to the arms, one‑by‑one, to form polymers. After each monomer addition, debris is removed by molecular sieving through specially designed membranes. The process is repeated until the desired sequence of monomers is reached, and then the exact-length-and-sequence polymers are cut off the hubs and recovered. NanoLink will use Nanostar Sieving to make PEGs, comprising sequences of Exactmer's completely-new, EG-based monomers, each containing a side-group designed to attach useful cargo. When polymerised, these monomers will form multi-functional PEGs (_mf_PEGs), and will be used as linkers for Antibody-Drug-Conjugates (ADCs). ADCs have been developed as a 'magic-bullet' for cancer treatment, delivering toxic payloads directly to cancer cells; bypassing healthy cells. By increasing water-solubility, drug-to-antibody ratios and enabling incorporation of multifunctional components, _mf_PEGs could revolutionise ADC therapeutics.

Polymers are long molecules comprising repeated chemical units known as monomers. Some polymers, such as polyethylene glycol (PEG), comprising ethylene glycol (Eg) monomers, are very useful parts of sophisticated nanomedicines, because they regulate the way that a medicine is transported around and retained in the body. Other polymers, including oligonucleotides (oligos) are used as therapeutic agents. It is extremely difficult to make polymers such as PEG and oligos accurately, because chemical techniques often add a few more or a few less monomers to the chain. For example, in making Eg112, a PEG polymer with 112 repeated units and a molecular weight close to 5kDa, current processes also make Eg111, Eg113, Eg110, Eg114, and so on, so that the material is known as polydisperse. This is a problem for use as part of a medicine, because the different chain lengths can act in different ways in the body, and analysis of multiple species is harder to do accurately. EXACTMER is a start-up company which has licensed a breakthrough new technology invented at Imperial College London- Nanostar Sieving. A hub molecule with three or more arms is used to form a macromolecular Nanostar. Monomers are added to each of the arms, one by one, to form polymers with an exactly controlled sequence of monomers. After the addition of each monomer, all the debris are removed by molecular sieving through a specially designed membrane. The process is repeated over and over until the desired number of monomers has been added, and then the polymers are cut off the hub and recovered, with all polymer molecules having the same, exact number and sequence of monomers. During 2019 we have sold small quantities (1g) of PEGs, and have carried out paid trials to show that Nanostar Sieving can produce purer oligos than conventional technology. We generated £235K in revenue, indicative of strong interest from a range of customers. Now we must quickly capitalise on this by innovating to make our process more efficient, and using it to make 10-20g batches. Success in this innovation project will provide the technical basis for EXACTMER to invest in 1kg scale manufacturing in 2022, rising to 10kg scale in 2023/24\. It will establish Nanostar Sieving as a competitor to the current state-of-the-art, expensive solid phase synthesis. Exactmer will strive to become the dominant global producer of exact, high value polymers, based in the UK.

Polymers are long molecules comprising repeated chemical units known as monomers. Some polymers, such as polyethylene glycol (PEG), comprising ethylene glycol (Eg) monomers, are very useful parts of sophisticated nanomedicines, because they regulate the way that a medicine is transported around and retained in the body. Chemically modified oligonucleotide polymers (oligos) are used as therapeutic agents for a variety of diseases (muscular dystrophy, hepatitis, atherosclerotic cardiovascular disease) and recent studies suggest they could potentially be used as antiviral or anti-inflammatory therapies for CoV infections. It is extremely difficult to make polymers such as PEGs and oligos accurately, because chemical techniques often add a few more or a few less monomers to the chain. For example, in making Eg112, a PEG polymer with 112 repeated units and a molecular weight close to 5kDa, current processes also make Eg111, Eg113, Eg110, Eg114, and so on, so that the material is known as polydisperse. This is a problem for use as part of a medicine, because the different chain lengths can act in different ways in the body, and analysis of multiple species is harder to do accurately. EXACTMER is a start-up company which has licensed a breakthrough new technology invented at Imperial College London- Nanostar Sieving. A hub molecule with three or more arms is used to form a macromolecular Nanostar. Monomers are added to each of the arms, one by one, to form polymers with an exactly controlled sequence of monomers. After the addition of each monomer, all the debris are removed by molecular sieving through a specially designed membrane. The process is repeated over and over until the desired number of monomers has been added, and then the polymers are cut off the hub and recovered, with all polymer molecules having the same, exact number and sequence of monomers. Nanostar Sieving can produce purer oligos than conventional solid phase synthesis methods; and because it is a liquid phase process it can be scaled to the kg-scale with a significant reduction of manufacturing costs. During 2019 we have carried out paid trials to show that Nanostar Sieving can produce purer oligos (our primary market) than conventional technology, and we have sold small quantities (1g) of PEGs (our secondary market). We generated £235K in revenue, indicative of strong interest from a range of customers. Now we must quickly capitalise on this by creating a single-stage separation synthesiser Nanostar-10, to make our process more efficient and reduce the solvent consumption. This synthesiser will be used to manufacture 10-20g batches of oligos and prove the process resource efficiency and scalability. Success in this innovation project will provide the technical basis for EXACTMER to invest in 1kg scale manufacturing in 2022, rising to 10kg scale in 2023/24\. This project will establish Nanostar Sieving as a competitor to the current state-of-the-art, expensive solid phase synthesis. Exactmer will strive to become the dominant global producer of exact, high value polymers, based in the UK.

no public description

"Polymers are long molecules comprising repeated chemical units known as monomers. Some polymers, such as polyethylene glycol (PEG), which comprises ethylene glycol (EG) monomers, are very useful as therapeutic agents and as parts of sophisticated nanomedicines, because they regulate the way that a medicine is transported around and retained in the body. Other polymers mimic naturally produced polymers including peptides and oligonucleotides (oligos). However it is extremely difficult to make polymers such as PEG and oligos accurately, because chemical techniques often add a few more or a few less monomers to the chain. For example, in making EG112, a PEG polymer with 112 repeated EG units and a molecular weight close to 5,000 Da, current processes also make EG111, EG113, EG110, EG114, and so on, so that the material is known as polydisperse. This is a problem when it comes to use as part of a medicine, because the different chain lengths can act in different ways in the body, and analysis of multiple species is harder to do accurately. EXACTMER is a start-up company that has licensed a new technology invented at Imperial College London, Nanostar Sieving. A hub molecule with three or more arms is used to form a macromolecular Nanostar. Monomers are added to each of the arms, one by one, to form polymers with an exactly controlled sequence of monomers. After the addition of each monomer, all the debris are removed by molecular sieving through a specially designed membrane. The process is repeated over and over until the desired number of monomers has been added, and then the polymers are cut off the hub and recovered, with all molecules having the same, exact number of monomers. This feasibility project aims to show that this completely new approach can scaled up to produce pure PEGs and oligonucleotides at scales of at least 10 g product per batch, and with rapid cycle times. If we are successful, this will be a breakthrough for PEG fabrication and will enable EXACTMER to launch a range of PEG products of high molecular weight and unprecedented purity. It will enable us to introduce Nanostar Sieving as an alternative to the widely used and expensive solid phase synthesis for peptides and oligonucleotides. We will develop Nanostar Sieving for the assembly of further, more sophisticated nanomedicines, and strive to become the UK based dominant global producer of exact, high value polymers."